Carboplatin in patients with metastatic castration-resistant prostate cancer harboring somatic or germline homologous recombination repair gene mutations: Phase II single-arm trial (the CIPHER trial).

Abstract

204 Background: Approximately one-fourth of patients with metastatic castration resistant prostate cancer (mCRPC) harbor mutations in homologous recombination repair (HRR) pathway genes. However, access to PARP inhibitors remains limited in LMICs. Carboplatin has been inadequately researched in such settings. Methods: We conducted a phase II single arm clinical trial at a tertiary care cancer centre in Northern India. Eligible patients harboring a mutation in the HRR pathway genes and previously treated with at least one androgen pathway receptor inhibitor, who did not have access to PARP inhibitors were treated with single agent carboplatin (dose: area under curve 5) every 3 weeks. The primary endpoint was PSA50 response, defined as a confirmed decline in serum levels of more than 50% from enrollment. Secondary endpoints included radiological response, and safety. Results: Of 213 patients with mCRPC screened for HRR mutations, 44 (20.6%) harbored a mutation in the HRR genes. Of these, 39 patients received carboplatin. The baseline characteristics are shown in the table. The primary end-point of PSA50 was observed in 41% patients. Among 30 evaluable patients for radiological responses, partial response occurred in 20.0%, and stable disease in 43.3%. The median duration of response was 6.2 months. In a multivariate analysis, patients with germline mutation were more likely to respond compared to those with somatic mutations (odds ratio, 6.76; P=0.05). Conclusions: In men with mCRPC harboring HRR mutations, carboplatin is associated with 41% PSA50 response rate, suggesting activity in this subset of patients. Patients with germline mutations are more likely to respond to carboplatin. In patients who do not have access to PARP inhibitors, use of carboplatin may be a reasonable option. Clinical trial information: CTRI/2023/04/051507 . Baseline characteristics (n=39). Characteristic Overall (N = 39) Age (years) median [min–max] 65 [52–81] PSA (ng/mL), median [min–max] 48.8 [2.3–1251.0] Family history Yes 11 (28.2%) ECOG Performance Status  0 12 (31.0%)  1 27 (69.0%) Volume*  High 33 (84.6%)  Low 6 (15.4%) Metastatic sites  Non regional Nodal involvement 26 (66.7%)  Visceral metastasis 7 (17.9%)  Lung metastasis 3 (7.7%)  Liver metastasis 5 (12.8%)  Skeletal metastasis 37 (94.9%) Pathology (Gleason score)  7 5 (12.8%)  8 18 (46.2%)  9 14 (35.9%)  10 2 (5.1%) Previous therapies  Abiraterone acetate (AA) 34 (87.2%)  Docetaxel (CSPC) 8 (20.5%)  Docetaxel (CRPC) 12 (30.8%)  Prior docetaxel (any) 20 (51.3%)  Enzalutamide 16 (41.0%)  Cabazitaxel 3 (7.7%)  Lu-177 PSMA therapy 3 (7.7%) Lines of prior systemic therapies  1 18 (46.2%)  2 15 (38.5%)  ≥ 3 6 (15.4%) Mutation type  Somatic mutation 23 (59.0%)  Germline mutation 16 (41.0%) HRR genes  BRCA2 11 (28.2%)  ATM 9 (23.1%)  BRCA1 6 (15.4%)  CDK12 3 (7.7%)  RAD54L 3 (7.7%)  BRIP1 2 (5.1%)  PALB2 2 (5.1%)  RAD51D 2 (5.1%)  AKT1 1 (2.6%)  BARD1 1 (2.6%)